A new entry to carbocyclic nucleosides: Oxidative coupling reaction of cycloalkenylsilanes with a nucleobase mediated by hypervalent iodine reagent

Article abstract of DOI:10.1021/ol8012155

(Chemical Equation Presented) A novel method for synthesizing carbocyclic nucleosides was developed. The new synthesis includes a direct coupling reaction of cycloalkenylsilanes with a silylated nucleobase catalyzed by a hypervalent iodine reagent. By app

Full text of DOI:10.1021/ol8012155

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3449-3452
A New Entry to Carbocyclic
Nucleosides: Oxidative Coupling
Reaction of Cycloalkenylsilanes with a
Nucleobase Mediated by Hypervalent
Iodine Reagent
Yuichi Yoshimura,*,† Masatoshi Ohta,† Tatsushi Imahori,† Tomozumi Imamichi,‡
and Hiroki Takahata*,†
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical UniVersity,
4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan, and Laboratory of Human
RetroVirology, Applied and DeVelopment Research Program, National Institute of
Allergy and Infectious Diseases at Frederick, Science Applications International
Corporation-Frederick, Inc., Frederick, Maryland 21702
yoshimura@tohoku-pharm.ac.jp
Received May 29, 2008
ABSTRACT
A novel method for synthesizing carbocyclic nucleosides was developed. The new synthesis includes a direct coupling reaction of
cycloalkenylsilanes with a silylated nucleobase catalyzed by a hypervalent iodine reagent. By applying the method, a novel carbocyclic cytidine
derivative having bis(hydroxymethyl)cyclohexene as a pseudosugar moiety, designed as a potential anti-HIV agent, was successfully synthesized.
Carbocyclic nucleosides are a unique class of nucleosides
in which ring oxygen atoms of sugars are replaced with
methylene groups. One of the most attractive characteristics
of carbocyclic nucleosides is their antiviral activities.1–4 Since
the discovery of the potent antihuman immunodeficiency
virus (HIV) activity of carbovir 1,1 a cyclopentene ring has
been recognized as a ribofuranose equivalent for designing
new anti-HIV nucleosides. For instance, cyclopentenylcy-
tosine 22 and bis[(hydroxymethyl)cyclopentenyl]adenine
(BCA) 33 were shown to possess anti-HIV activities. A
cyclohexenyl nucleoside, a homologue of cyclopentenyl
nucleosides, is also interesting: cyclohexenylguanine 4 is
known to have anti-human herpes simplex virus type 1
(HSV-1) activity.4
As one part of our continuous study to search for new
anti-HIV agent,5 the synthesis of a novel cycloalkenyl
nucleoside was envisioned. The direct introduction of a
† Tohoku Pharmaceutical University.
‡ Science Applications International Corporation-Frederick.
(1) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17
.
(5) (a) Yamada, K.; Sakata, S.; Yoshimura, Y. J. Org. Chem. 1998, 63,
6891. (b) Yoshimura, Y.; Asami, K.; Matsui, H.; Tanaka, H.; Takahata, H.
Org. Lett. 2006, 8, 6015. (c) Yoshimura, Y.; Yamazaki, Y.; Kawahata, M.;
Yamaguchi, K.; Takahata, H. Tetrahedron Lett. 2007, 48, 4519.
(6) Typically, Mitsunobu reaction and Pd-catalyzed cross-coupling
reaction have been used:(a) Barral, K.; Halfon, P.; Pe`pe, G.; Camplo, M.
Tetrahedron Lett. 2002, 43, 81. (b) Trost, B. M.; Li, L.; Guile, S. D. J. Am.
Chem. Soc. 1992, 114, 8745.
(2) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.; Schinazi,
R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3985
.
(3) Katagiri, N.; Shiraishi, T.; Sato, H.; Toyota, A.; Kaneko, C.; Yusa,
K.; Oh-hara, T.; Tsuruno, T. Biochem. Biophys. Res. Commun. 1992, 184,
154
.
(4) Wang, J.; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Herdewijn, P. J. Med. Chem. 2000, 43, 736
.
10.1021/ol8012155 CCC: $40.75
Published on Web 07/10/2008
2008 American Chemical Society

nucleobase to a precursor for pseudosugar is the most
straightforward access to the target carbocyclic nucleosides.6
We decided to explore a new oxidative coupling reaction
of cyclic allylsilane with a persilylated nucleobase that could
be applied to the synthesis of cycloalkenyl nucleosides. For
that, reaction using a hypervalent iodine reagent7 was tried
(Scheme 1). To our knowledge, there has been only one
Scheme 3
.
Oxidative Coupling Reaction of Cycloalkenylsilane
with Uracil
Scheme 1. New Access for Carbocyclic Nucleosides
reaction using [hydroxyl(tosyloxy)iodo]benzene gave 9b in
a poor yield (entry 7).
report on a C-N bond formation by a hypervalent iodine
reagent.7b
Table 1. Summary of the Oxidative Coupling Reaction of
Cycloalkenylsilane and Uracil
First, an oxidative coupling reaction was examined by a
model reaction using simple cycloalkenylsilanes. Cyclopent-
2-enylsilanes 7a, 8a and cyclohex-2-enylsilanes 7b, 8b were
prepared by hydrosilylation8 of cyclopentadiene and cyclo-
hexadiene, respectively (Scheme 2). Along with our initial
entry
silane
I(III)
time (h)
yield (%)
1
2
3
4
5
6
7
7a
7b
8a
8b
8b
8b
8b
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(O2CCF3)2
PhIO
15
15
1
1
1
45
49
65
65
55
57
29
1
1
Scheme 2. Synthesis of Cycloalkenylsilane
PhI(OH)OTs
As considered from the chemistry of hypervalent iodine,
the coupling reaction should proceed via an allyl cation
generated by the reaction of (diacetoxyiodo)benzene and
allylsilane. To prove the reaction mechanism, we envisaged
performing the oxidative coupling reaction using chiral
alkenylsilane.
Enantioselective hydrosilylation of 5b using chiral (R)-
Ar-MOP ligand, which has been developed by Hayashi and
Uozumi,9 gave (S)-6b in 74% yield with 56-66% ee.
Compound (S)-6b was converted to (S)-7b and (S)-8b as
described above (Scheme 4).
plan, the coupling reaction of 7 and 8 with persilylated uracil
in the presence of a hypervalent iodine reagent and TMSOTf
was examined (Scheme 3). The results are summarized in
Table 1.
To our delight, the reactions of allylsilanes 7a and 7b with
persilylated uracil in the presence of (diacetoxyiodo)benzene
gave cycloalkenyluracils 9a and 9b in 45% and 49% yields,
respectively (entries 1 and 2). Because of the slow reaction
and the formation of side products, the use of triethoxysilanes
was abandoned, and reactions using trimethylsilyl derivatives
were next examined. Treatment of allyltrimethylsilanes 8a
and 8b under the same conditions as those described above
gave 9a and 9b in 65% yield (entries 3 and 4). Oxidative
coupling reactions of 8b with various hypervalent iodine
reagents were also attempted. The use of [di(trifluoroac-
etoxy)iodo]benzene and iodosobenzene slightly diminished
the reaction yields (entries 5 and 6). On the other hand, the
Scheme 4
.
Enantioselective Synthesis of Chiral
Cyclohexenylsilanes
(7) (a) Ochiai, M.; Fujita, E.; Arimoto, M.; Yamaguchi, H. Chem. Pharm.
Bull. 1985, 33, 41. (b) Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenaga,
N.; Kita, Y. Chem. Commun. 2007, 1224. (c) Dohi, T.; Morimoto, K.;
Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y.
J. Org. Chem. 2007, 72, 109.
The oxidative coupling reaction of both (S)-7b and (S)-
8b gave a racemic mixture of cyclohexenyluracil 9b as
(9) Hayashi, T.; Han, J. W.; Takeda, A.; Tang, J.; Nohmi, K.; Mukaide,
K.; Tsuji, H.; Uozumi, Y. AdV. Synth. Catal. 2001, 343, 279.
(8) Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989, 30, 1099.
3450
Org. Lett., Vol. 10, No. 16, 2008

Chart 1
Scheme 6. Synthesis of
Di(hydroxymethyl)trimethylsilylcyclohexene
The Diels-Alder reaction of trimethylsilylbutadiene 11
and dimethyl fumarate 12 gave cyclohexene diester 13 as a
1:1 mixture of endo/exo isomers in good yield.11 Hydride
reduction of 13 and subsequent separation by silica gel
column chromatography gave 1,2-trans-adduct 14a and 1,2-
syn-adduct 14b in 49% and 50% yields, respectively.
Compounds 14a and 14b were protected by the silyl group
to give di-TBDPS derivatives 15a and 15b quantitatively.
The relative stereochemistry of 14a and 14b was determined
by 1H NMR after being reduced to the corresponding
cycloalkane derivatives (data not shown).
anticipated. This result strongly supports the formation of
the ally cation intermediate that we presumed (Scheme 5).
Scheme 5
.
Oxidative Coupling Reaction Using Chiral
Cyclohexenylsilane
The coupling reaction of 15a and 15b with persilylated
uracil was tried by using (diacetoxyiodo)benzene as an
oxidant (Scheme 7). The results are shown in Table 2. Since
the reaction is considered to proceed via an allyl cation, it
was anticipated that the reaction would give a mixture of
stereoisomers including regioisomers. Indeed, the reaction
of 15a gave an inseparable mixture containing four stere-
We next focused on the application of the oxidative
coupling reaction to the synthesis of new carbocyclic
nucleoside derivatives designed as potential anti-HIV agents.
The target molecule we selected was carbocyclic cytidines
10a-d constructed on a cyclohexenyl scaffold as depicted
in Chart 2.10 Diels-Alder reaction would be suitable for
1
oisomers with a ratio of 6:10:2:1.5 estimated from the H
NMR spectrum, and the reaction of 15b gave a similar result.
Cyclohexadiene 17 obtained in both cases was thought to
be formed by E1 elimination of the ally cation intermediate.
It was difficult to determine their structures at this stage.
Thus, the structures of the products were elucidated after
conversion and isolation to final products (vide infra).
It is also interesting that 15a and 15b showed different
reactivities under the oxidative coupling reaction. Probably,
some steric interaction of the substituents on the cyclohexene
ring would exist, but the details are not clear yet.
Chart 2
To separate stereoisomers of the cyclohexenyluracils, we
tried temporary N3-benzoylation of 16a-d. Treatment of
16a-d with benzoyl chloride and triethylamine gave a
mixture of 18a-d, which was subjected to separation by
silica gel column chromatography to afford 18a, 18d, and a
mixture of 18b and 18c. After debenzoylation, the com-
pounds 16a-d thus obtained were treated with 2,4,6-
triisopropylbenzenesulfonyl chloride (TPSCl) followed by
preparing the substrate of oxidative coupling, which would
lead to 10a-d, since installation of a trimethylsilyl group
and stereoselective introduction of trans-dihydroxymethyl
groups could be achieved in a single step.
(10) The synthesis of the purine derivatives of 10a has been reported:
˚
Rosenquist, A; Kvarnstro¨m, I.; Classon, B.; Samuelsson, B. J. Org. Chem.
(11) Jung, M. E.; Gaede, B. Tetrahedron 1979, 35, 621.
(12) Sekine, M.; Matsuzaki, J.; Satoh, M.; Hata, T. J. Org. Chem. 1982,
47, 571.
1996, 61, 6382. Although those were reported to be inactive against HIV,
the anti-HIV activitiy of the pyrimidine derivatives has not been investigated.
Additionally, 10c,d were considered to be a new class of carbocyclic
nucleosides.
(13) Anti-HIV-1 activities of the compounds were evaluated by sup-
pression of HIV replication in PBMCs by p24 antigen capture assay.
Org. Lett., Vol. 10, No. 16, 2008
3451

Table 2. Summary of the Oxidative Coupling Reaction of
15a/15b and Uracil
Scheme 8. Synthesis of cyclohexenylcytosines 10a-d
yield (%)
ratio
compd
time (h)
16a-d
17
recov
16a:16b:16c:16d
15a
15b
1
24
60
50
18
11
0
20
6:10:2.0:1.5
3:10:2.5:0.5
aqueous ammonia to give cytidine derivatives 19a-d.12 At
this step, all stereoisomers could be completely separated.
Finally, desilylation of 19a-d gave desired 10a-d in good
yields.
From 2D-NMR data and NOE experiments, the structures
of 10b and 10c were determined as shown in Figure 1 in
Supporting Information. As a result, the structures of 10a
and 10d were estimated as depicted in Scheme 8. The
stereochemical outcome of the oxidative coupling of allyl-
silane 15a/b with uracil could be explained by steric
interactions depicted in Figure 2 in Supporting Information.
Nucleophilic attack to the less hindered γ-carbon from the
up side in the figure that would lead to formation of 16b
would be preferable.
Anti-HIV activities of 10a-d were evaluated, and it was
found that only 10b inhibited HIV replication in peripheral
blood mononuclear cells (PBMC) with 39% inhibition at 10
µM.13 The other three isomers were inactive against HIV-1.
In conclusion, we have developed a novel oxidative
coupling reaction for synthesizing carbocyclic nucleosides
based on hypervalent iodine chemistry. By applying the
reaction, new carbocyclic cytidine derivatives were synthe-
sized, and the major product was found to have anti-HIV
activity. Determination of an active enantiomer is our next
problem to be solved.
Scheme 7. Oxidative Coupling Reaction of 15a/15b and Uracil
Acknowledgment. This work was supported, in part, by
a Grant-in-Aid for Scientific Research (No. 18590103) (Y.Y.)
and by the High Technology Research Program from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
Supporting Information Available: Figures 1 and 2,
experimental procedures, characterization data, and NMR
charts (1H and 13C). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL8012155
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Org. Lett., Vol. 10, No. 16, 2008